tbuckley/cabot-search huggingface dataset:
Limonoids from neem (<i>Azadirachta indica</i> A. Juss.) are potential anticancer drug candidates
Authors: Siddavaram Nagini, Manikandan Palrasu, Anupam Bishayee
Journal: Medicinal Research Reviews (2023)

Abstract Neem ( Azadirachta indica A. Juss.), a versatile evergreen tree recognized for its ethnopharmacological value, is a rich source of limonoids of the triterpenoid class, endowed with potent medicinal properties. Extracts of neem have been documented to display anticancer effects in diverse malignant cell lines as well as in preclinical animal models that has largely been attributed to the constituent limonoids. Of late, neem limonoids have become the cynosure of research attention as potential candidate agents for cancer prevention and therapy. Among the various limonoids found in neem, azadirachtin, epoxyazadiradione, gedunin, and nimbolide, have been extensively investigated for anticancer activity. Azadirachtin, a potent biodegradable pesticide, exhibits profound antiproliferative effects by preventing mitotic spindle formation and cell division. The antiproliferative activity of gedunin has been demonstrated to be mediated primarily via inhibition of heat shock protein90 and its client proteins. Epoxyazadiradione inhibits pro‐inflammatory and kinase‐driven signaling pathways to block tumorigenesis. Nimbolide, the most potent cytotoxic neem limonoid, inhibits the growth of cancer cells by regulating the phosphorylation of keystone kinases that drive oncogenic signaling besides modulating the epigenome. There is overwhelming evidence to indicate that neem limonoids exert anticancer effects by preventing the acquisition of hallmark traits of cancer, such as cell proliferation, apoptosis evasion, inflammation, invasion, angiogenesis, and drug resistance. Neem limonoids are value additions to the armamentarium of natural compounds that target aberrant oncogenic signaling to inhibit cancer development and progression.
Emergency Department Use Across Income Groups Following an Increase in Cost-Sharing
Authors: Yushan Wu, Dorothy Yingxuan Wang, Shi Zhao, Maggie Haitian Wang, Eliza Lai-yi Wong, Eng-kiong Yeoh
Journal: JAMA Network Open (2023)

To encourage the appropriate utilization of emergency care, cost-sharing for emergency care was increased from HK$100 (US $12.8) to HK$180 (US $23.1) per visit in June 2017 in all public hospitals in Hong Kong. However, there are concerns that this increase could deter appropriate emergency department (ED) visits and be associated with income-related disparities.To examine changes in ED visits after the fee increase.This retrospective cohort study used administrative data from June 2015 to May 2019 from all public hospitals in Hong Kong. Participants included all Hong Kong residents aged 64 years and younger, categorized into low-income, middle-income, and high-income groups according to the median household income in their district of residence. Data analysis was performed from May to June 2023.The primary outcome was the ED visit rate per 100 000 people per month, categorized into 3 severity levels (emergency, urgent, and nonurgent). Secondary outcomes include general outpatient (GOP) visit rate, emergency admission rate, and in-hospital mortality rate per month at public hospitals. Segmented regression analyses were used to estimate changes in the level and slope of outcome variables before and after the fee increase.This study included a total of 5 441 679 ED patients (2 606 332 male patients [47.9%]; 2 108 933 patients [38.5%] aged 45-64 years), with 2 930 662 patients (1 407 885 male patients [48.0%]; 1 111 804 patients [37.9%] aged 45-64 years) from the period before the fee increase. The fee increase was associated with an 8.0% (95% CI, 7.1%-9.0%) immediate reduction in ED visits after June 2017, including a 5.9% (95% CI, 3.3%-8.5%) reduction in urgent visits and an 8.9% (95% CI, 8.0%-9.8%) reduction in nonurgent visits. In addition, a 5.7% (95% CI, 4.7%-6.8%) reduction of emergency admissions was found, whereas no significant changes were observed in in-hospital mortality. Specifically, a statistically significant increase in GOP visits (4.1%; 95% CI, 0.9%-7.2%) was found within the low-income group, but this association became insignificant after controlling for the social security group, who were exempted from payment, as a control.In this cohort study, the fee increase was not associated with changes in ED visits for emergency conditions, but there was a negative and significant association with both urgent and nonurgent conditions across all income groups. Considering the marginal increase in public GOP services, further study is warranted to examine strategies to protect low-income people from avoiding necessary care.
Phase I study evaluating the Fc-optimized FLT3 antibody FLYSYN in AML patients with measurable residual disease
Authors: Jonas S. Heitmann, Richard F. Schlenk, Daniela Dörfel, Sabine Kayser, Konstanze Döhner, Michael Heuser, Felicitas Thol, Silke Kapp-Schwoerer, Jannik Labrenz, Dominic Edelmann, Melanie Märklin, Wichard Vogel, Wolfgang Bethge, Juliane S. Walz, Ludger Große-Hovest, Martin Steiner, Gundram Jung, Helmut R. Salih
Journal: Journal of Hematology & Oncology (2023)

About half of AML patients achieving complete remission (CR) display measurable residual disease (MRD) and eventually relapse. FLYSYN is an Fc-optimized antibody for eradication of MRD directed to FLT3/CD135, which is abundantly expressed on AML cells.This first-in-human, open-label, single-arm, multicenter trial included AML patients in CR with persisting or increasing MRD and evaluated safety/tolerability, pharmacokinetics and preliminary efficacy of FLYSYN at different dose levels administered intravenously (cohort 1-5: single dose of 0.5 mg/m2, 1.5 mg/m2, 5 mg/m2, 15 mg/m2, 45 mg/m2; cohort 6: 15 mg/m2 on day 1, 15 and 29). Three patients were treated per cohort except for cohorts 4 and 6, which were expanded to nine and ten patients, respectively. Primary objective was safety, and secondary efficacy objective was ≥ 1 log MRD reduction or negativity in bone marrow.Overall, 31 patients were treated, of whom seven patients (22.6%) experienced a transient decrease in neutrophil count (two grade 3, others ≤ grade 2). No infusion-related reaction or dose-limiting toxicity was observed. Adverse events (AEs) were mostly mild to moderate, with the most frequent AEs being hematologic events and laboratory abnormalities. Response per predefined criteria was documented in 35% of patients, and two patients maintained MRD negativity until end of study. Application of 45 mg/m2 FLYSYN as single or cumulative dose achieved objective responses in 46% of patients, whereas 28% responded at lower doses.FLYSYN monotherapy is safe and well-tolerated in AML patients with MRD. Early efficacy data are promising and warrant further evaluation in an up-coming phase II trial. Trial registration This clinical is registered on clinicaltrials.gov (NCT02789254).
Glycopolymers With On/Off Anchors: Confinement Effect on Regulating Dendritic Cells
Authors: Xingyu Heng, Fangjian Shan, He Yang, Jun Hu, Ruyan Feng, Wende Tian, Gaojian Chen, Hong Chen
Journal: Advanced Healthcare Materials (2023)

Insufficient activation or over-activation of T cells due to the dendritic cells (DCs) state can cause negative effects on immunotherapy, making it crucial for DCs to maintain different states in different treatments. Polysaccharides are one of the most studied substances to promote DCs maturation. However, in many methods, optimizing the spatial dimension of the interaction between polysaccharides and cells is often overlooked. Therefore, in this study, a new strategy from the perspective of spatial dimension is proposed to regulate the efficacy of polysaccharides in promoting DCs maturation. An anchoring molecule (DMA) is introduced to existing glycopolymers for the confinement effect, and the effect can be turned off by oxidation of DMA. Among the prepared on-confined (PMD2 ), off-confined (PMD2 -O), and norm (PM2 ) glycopolymers, PMD2 and PMD2 -O show the best and worst results, respectively, in terms of the amount of binding to DCs and the effect on promoting DCs maturation. This sufficiently shows that the turn-on and off of confinement effect can regulate the maturation of DCs by polysaccharides. Based on the all-atom molecular dynamics (MD) simulation, the mechanism of difference in the confinement effect is explained. This simple method can also be used to regulate other molecule-cell interactions to guide cell behavior.
Augmented Reality for Perioperative Anxiety in Patients Undergoing Surgery
Authors: Michael G. Rizzo, Joseph P. Costello, Dylan Luxenburg, Jacob L. Cohen, Nicolas Alberti, Lee D. Kaplan
Journal: JAMA Network Open (2023)

Both augmented reality (AR) and virtual reality (VR) have had increasing applications in medicine, including medical training, psychology, physical medicine, rehabilitation, and surgical specialties, such as neurosurgery and orthopedic surgery. There are little data on AR's effect on patients' anxiety and experiences.To determine whether the use of an AR walkthrough effects patient perioperative anxiety.This randomized clinical trial was conducted at an outpatient surgery center in 2021 to 2022. All patients undergoing elective orthopedic surgery with the senior author were randomized to the treatment or control group. Analyses were conducted per protocol. Data analysis was performed in November 2022.AR experience explaining to patients what to expect on their day of surgery and walking them through the surgery space. The control group received the standard educational packet.The main outcome was change in State-Trait Anxiety Inventory (STAI) from the screening survey to the preoperative survey.A total of 140 patients were eligible, and 45 patients either declined or were excluded. Therefore, 95 patients (63 [66.3%] male; mean [SD] age, 38 [16] years) were recruited for the study and included in the final analysis; 46 patients received the AR intervention, and 49 patients received standard instructions. The AR group experienced a decrease in anxiety from the screening to preoperative survey (mean score change, -2.4 [95% CI, -4.6 to -0.3]), while the standard care group experienced an increase (mean score change, 2.6 [95% CI, 0.2 to 4.9]; P = .01). All patients postoperatively experienced a mean decrease in anxiety score compared with both the screening survey (mean change: AR, -5.4 [95% CI, -7.9 to -2.9]; standard care, -6.9 [95% CI, -11.5 to -2.2]; P = .32) and preoperative survey (mean change: AR, -8.0 [95% CI, -10.3 to -5.7]; standard care, -4.2 [95% CI, -8.6 to 0.2]; P = .19). Of 42 patients in the AR group who completed the postoperative follow-up survey, 30 (71.4%) agreed or strongly agreed that they enjoyed the experience, 29 (69.0%) agreed or strongly agreed that they would recommend the experience, and 28 (66.7%) agreed or strongly agreed that they would use the experience again. No differences were observed in postoperative pain levels or narcotic use.In this randomized clinical trial, the use of AR decreased preoperative anxiety compared with traditional perioperative education and handouts, but there was no significant effect on postoperative anxiety, pain levels, or narcotic use. These findings suggest that AR may serve as an effective means of decreasing preoperative patient anxiety.ClinicalTrials.gov Identifier: NCT04727697.
Lorazepam Stimulates IL6 Production and Is Associated with Poor Survival Outcomes in Pancreatic Cancer
Authors: Abigail C. Cornwell, Arwen A. Tisdale, Swati Venkat, Kathryn E. Maraszek, Abdulrahman A. Alahmari, Anthony George, Kristopher Attwood, Madison George, Donald Rempinski, Janusz Franco-Barraza, Mukund Seshadri, Mark D. Parker, Eduardo Cortes Gomez, Christos Fountzilas, Edna Cukierman, Nina G. Steele, Michael E. Feigin
Journal: Clinical Cancer Research (2023)

This research investigates the association between benzodiazepines (BZD) and cancer patient survival outcomes, the pancreatic cancer tumor microenvironment, and cancer-associated fibroblast (CAF) signaling.Multivariate Cox regression modeling was used to retrospectively measure associations between Roswell Park cancer patient survival outcomes and BZD prescription records. IHC, H&E, Masson's trichrome, RNAscope, and RNA sequencing were used to evaluate the impact of lorazepam (LOR) on the murine PDAC tumor microenvironment. ELISA and qPCR were used to determine the impact of BZDs on IL6 expression or secretion by human-immortalized pancreatic CAFs. PRESTO-Tango assays, reanalysis of PDAC single-cell sequencing/TCGA data sets, and GPR68 CRISPRi knockdown CAFs were used to determine the impact of BZDs on GPR68 signaling.LOR is associated with worse progression-free survival (PFS), whereas alprazolam (ALP) is associated with improved PFS, in pancreatic cancer patients receiving chemotherapy. LOR promotes desmoplasia (fibrosis and extracellular matrix protein deposition), inflammatory signaling, and ischemic necrosis. GPR68 is preferentially expressed on human PDAC CAFs, and n-unsubstituted BZDs, such as LOR, significantly increase IL6 expression and secretion in CAFs in a pH and GPR68-dependent manner. Conversely, ALP and other GPR68 n-substituted BZDs decrease IL6 in human CAFs in a pH and GPR68-independent manner. Across many cancer types, LOR is associated with worse survival outcomes relative to ALP and patients not receiving BZDs.We demonstrate that LOR stimulates fibrosis and inflammatory signaling, promotes desmoplasia and ischemic necrosis, and is associated with decreased pancreatic cancer patient survival.
Financial Conflicts of Interest in Public Comments on Medicare National Coverage Determinations of Medical Devices
Authors: Angela Lu, Robin Z. Ji, Alex Y. Ge, Joseph S. Ross, Reshma Ramachandran, Rita F. Redberg, Sanket S. Dhruva
Journal: JAMA (2023)

This study reviewed public comments for all Medicare National Coverage Determinations between June 2019 and 2022 on select pulmonary and cardiac devices to determine whether financial conflicts of interest were disclosed.
Quantitative Microbial Risk Assessment of Contracting COVID-19 Derived from Measured and Simulated Aerosol Particle Transmission in Aircraft Cabins
Authors: Jack F. Schijven, Theo van Veen, Christiaan Delmaar, Johan Kos, Lucie Vermeulen, Rui Roosien, Frank Verhoeven, Maarten Schipper, Bram Peerlings, Erwin Duizer, Jonathan Derei, Wim Lammen, Onno Bartels, Harmen van der Ven, Robert Maas, Ana Maria de Roda Husman
Journal: Environmental Health Perspectives (2023)

Background: SARS-CoV-2 can be effectively transmitted between individuals located in close proximity to each other for extended durations. Aircraft provide such conditions. Although high attack rates during flights were reported, little was known about the risk levels of aerosol transmission of SARS-CoV-2 in aircraft cabins. Objectives: The major objective was to estimate the risk of contracting COVID-19 from transmission of aerosol particles in aircraft cabins. Methods: In two single-aisle and one twin-aisle aircraft, dispersion of generated aerosol particles over a seven-row economy class cabin section was measured under cruise and taxi conditions and simulated with a computational fluid dynamic model under cruise conditions. Using the aerosol particle dispersion data, a quantitative microbial risk assessment was conducted for scenarios with an asymptomatic infectious person expelling aerosol particles by breathing and speaking. Effects of flight conditions were evaluated using generalized additive mixed models. Results: Aerosol particle concentration decreased with increasing distance from the infectious person, and this decrease varied with direction. On a typical flight with an average shedder, estimated mean risk of contracting COVID-19 ranged from 1.3×10−3 to 9.0×10−2. Risk increased to 7.7×10−2 with a super shedder (<3% of cases) on a long flight. Risks increased with increasing flight duration: 2–23 cruise flights of typical duration and 2–10 flights of longer duration resulted in at least 1 case of COVID-19 due to onboard aerosol transmission by one average shedder, and in the case of one super shedder, at least 1 case in 1–3 flights of typical duration cruise and 1 flight of longer duration. Discussion: Our findings indicate that the risk of contracting COVID-19 by aerosol transmission in an aircraft cabin is low, but it will not be zero. Testing before boarding may help reduce the chance of a (super)shedder boarding an aircraft and mask use further reduces aerosol transmission in the aircraft cabin. https://doi.org/10.1289/EHP11495
Crocetin Regulates Functions of Neural Stem Cells to Generate New Neurons for Cerebral Ischemia Recovery (Adv. Healthcare Mater. 20/2023)
Authors: Zhongqing Liu, Zhaojun Wang, Zhanchi Zhu, Jing Hong, Leisha Cui, Ying Hao, Guosheng Cheng, Rui Tan
Journal: Advanced Healthcare Materials (2023)

Crocetin In article 2203132 by Ying Hao, Guosheng Cheng, Rui Tan, and co-workers, Crocetin, naturally extracted from the plant Saffron, acts as a neuroprotective agent for neurodegenerative diseases. It can activate subventricular zone neurogenesis and neuronal precursor differentiation in the damaged cortex and striatum sites to repair injured neurons and enhance the functional motor behavior of ischemic stroke rats.
Lymph node-targeting adjuvant/neoantigen-codelivering vaccines for combination glioblastoma radioimmunotherapy
Authors: Ting Su, Shurong Zhou, Suling Yang, Nicholas Humble, Fuwu Zhang, Guocan Yu, Paula D. Bos, Furong Cheng, Kristoffer Valerie, Guizhi Zhu
Journal: Theranostics (2023)

Glioblastoma multiforme (GBM) is the most common and lethal type of adult brain cancer. Current GBM standard of care, including radiotherapy, often ends up with cancer recurrence, resulting in limited long-term survival benefits for GBM patients. Immunotherapy, such as immune checkpoint blockade (ICB), has thus far shown limited clinical benefit for GBM patients. Therapeutic vaccines hold great potential to elicit anti-cancer adaptive immunity, which can be synergistically combined with ICB and radiotherapy. Peptide vaccines are attractive for their ease of manufacturing and stability, but their therapeutic efficacy has been limited due to poor vaccine co-delivery and the limited ability of monovalent antigen vaccines to prevent tumor immune evasion. To address these challenges, here, we report GBM radioimmunotherapy that combines radiotherapy, ICB, and multivalent lymph-node-targeting adjuvant/antigen-codelivering albumin-binding vaccines (AAco-AlbiVax). Specifically, to codeliver peptide neoantigens and adjuvant CpG to lymph nodes (LNs), we developed AAco-AlbiVax based on a Y-shaped DNA scaffold that was site-specifically conjugated with CpG, peptide neoantigens, and albumin-binding maleimide-modified Evans blue derivative (MEB). As a result, these vaccines elicited antitumor immunity including neoantigen-specific CD8+ T cell responses in mice. In orthotopic GBM mice, the combination of AAco-AlbiVax, ICB, and fractionated radiation enhanced GBM therapeutic efficacy. However, radioimmunotherapy only trended more efficacious over radiotherapy alone. Taken together, these studies underscore the great potential of radioimmunotherapy for GBM, and future optimization of treatment dosing and scheduling would improve the therapeutic efficacy.
pH-Weighted amine chemical exchange saturation transfer echo planar imaging visualizes infiltrating glioblastoma cells
Authors: Kunal S Patel, Jingwen Yao, Nicholas S Cho, Francesco Sanvito, Kaleab Tessema, Alvaro Alvarado, Lindsey Dudley, Fausto Rodriguez, Richard Everson, Timothy F Cloughesy, Noriko Salamon, Linda M Liau, Harley I Kornblum, Benjamin M Ellingson
Journal: Neuro-Oncology (2023)

Abstract Background Given the invasive nature of glioblastoma, tumor cells exist beyond the contrast-enhancing (CE) region targeted during treatment. However, areas of non-enhancing (NE) tumors are difficult to visualize and delineate from edematous tissue. Amine chemical exchange saturation transfer echo planar imaging (CEST-EPI) is a pH-sensitive molecular magnetic resonance imaging technique that was evaluated in its ability to identify infiltrating NE tumors and prognosticate survival. Methods In this prospective study, CEST-EPI was obtained in 30 patients and areas with elevated CEST contrast (“CEST+” based on the asymmetry in magnetization transfer ratio: MTRasym at 3 ppm) within NE regions were quantitated. Median MTRasym at 3 ppm and volume of CEST + NE regions were correlated with progression-free survival (PFS). In 20 samples from 14 patients, image-guided biopsies of these areas were obtained to correlate MTRasym at 3 ppm to tumor and non-tumor cell burden using immunohistochemistry. Results In 15 newly diagnosed and 15 recurrent glioblastoma, higher median MTRasym at 3ppm within CEST + NE regions (P = .007; P = .0326) and higher volumes of CEST + NE tumor (P = .020; P &amp;lt; .001) were associated with decreased PFS. CE recurrence occurred in areas of preoperative CEST + NE regions in 95.4% of patients. MTRasym at 3 ppm was correlated with presence of tumor, cell density, %Ki-67 positivity, and %CD31 positivity (P = .001; P &amp;lt; .001; P &amp;lt; .001; P = .001). Conclusions pH-weighted amine CEST-EPI allows for visualization of NE tumor, likely through surrounding acidification of the tumor microenvironment. The magnitude and volume of CEST + NE tumor correlates with tumor cell density, degree of proliferating or “active” tumor, and PFS.
The oncogenic human B-cell lymphoma MYD88 L265P mutation genocopies activation by phosphorylation at the Toll/interleukin-1 receptor (TIR) domain
Authors: Marthe Minderman, Hildo Lantermans, Carmen van der Zwaan, Arie J. Hoogendijk, Maartje van den Biggelaar, Marie José Kersten, Marcel Spaargaren, Steven T. Pals
Journal: Blood Cancer Journal (2023)

Abstract MYD88 is the key signaling adaptor-protein for Toll-like and interleukin-1 receptors. A somatic L265P mutation within the Toll/interleukin-1 receptor (TIR) domain of MYD88 is found in 90% of Waldenström macroglobulinemia cases and in a significant subset of diffuse large B-cell lymphomas. MYD88-L265P strongly promotes NF-κB pathway activation, JAK-STAT signaling and lymphoma cell survival. Previous studies have identified other residues of the TIR-domain crucially involved in NF-κB activation, including serine 257 (S257), indicating a potentially important physiological role in the regulation of MYD88 activation. Here, we demonstrate that MYD88 S257 is phosphorylated in B-cell lymphoma cells and that this phosphorylation is required for optimal TLR-induced NF-κB activation. Furthermore, we demonstrate that a phosphomimetic MYD88-S257D mutant promotes MYD88 aggregation, IRAK1 phosphorylation, NF-κB activation and cell growth to a similar extent as the oncogenic L265P mutant. Lastly, we show that expression of MYD88-S257D can rescue cell growth upon silencing of endogenous MYD88-L265P expression in lymphoma cells addicted to oncogenic MYD88 signaling. Our data suggest that the L265P mutation promotes TIR domain homodimerization and NF-κB activation by copying the effect of MY88 phosphorylation at S257, thus providing novel insights into the molecular mechanism underlying the oncogenic activity of MYD88-L265P in B-cell malignancies.